ABSTRACT ? OVERALL PROGRAM More than 25 million Americans suffer from asthma, and nearly half do not have their asthma under control. Standard treatment is limited, and a stepped care approach is applied uniformly to all patients regardless of the underlying mechanisms of asthma. Our Asthma Inflammation Research [AIR] Program aims to uncover fundamental mechanisms of asthma and identify biomarkers of those pathways that will define mechanistic endotypes of asthma in order to target therapies in a precision medicine approach of care. In Cycle I of the TPPG, we uncovered new mechanisms of airway inflammation and hyper-reactivity. In Cycle II, we apply the fundamental discoveries to precisely target pathways for bronchodilation (Project 3) and inflammation (Projects 1 and 2). Based on findings that oxidative metabolism mechanistically contributes to asthma, Project 1 investigates whether diet can modulate inflammatory responses, gene expression, and airway reactivity. Metabolic endotypes will be elucidated, and a specific biomarker of eosinophil activation, bromotytrosine (BrTyr) is tested in asthma control and biologic-based therapies of asthma. Project 2 has identified T-Helper 17 [TH17] pathways in origins of severe asthma. In Cycle II, Project 2 determines if, and how, TH17 cytokines drive pathologic inflammation, and uses the information to develop serum biomarkers of this endotype, and small molecule inhibitors and peptidomimetics of IL-17A for treatment of asthma. Project 3 shows that high levels of nitric oxide (NO) and oxidants in asthmatic airways damage soluble guanylate cyclase (sGC), making it NO-insensitive and diminishing the NO-sGC pathway from acting in bronchodilation. In Cycle II, Project 3 develops bronchodilator drug response profiling to identify sGC endotypes, and tests sGC activators and stimulators in asthma preclinical models to support a new indication for sGC drugs as bronchodilators. The projects benefit from model systems and efficiencies of cores, including a new Technology Development and Commercialization Core B, and innovative murine models of asthma and airflow imaging in Core C. Partnerships with Pharmaceutical & Biotechnology, Nutrition, Health & Wellness companies, and strategic leveraging of Cleveland-based NHLBI National Centers for Accelerating Innovation (NCAI-CC) and the NSF Innovations Corps at Cleveland Clinic ensure that our discoveries will be implemented over the next 5 years. Altogether, the program provides an unparalleled opportunity for efficient progression of personalized asthma care products to the marketplace for patients.